Cardiovascular Risk Reduction in Patients with Chronic Kidney Disease

Clinical Review Article Series Editor: Mark A. Perazella, MD, FACP

CKD Series: Cardiovascular Risk Reduction in Patients with Chronic Kidney Disease Maria Criselda Zaldivar, MD Aldo J. Peixoto, MD ardiovascular disease is the leading cause of death in patients with chronic kidney disease (CKD) regardless of stage.1 Forty percent to 50% of all deaths in the end-stage renal disease (ESRD) population are of cardiovascular origin.1 Cardiovascular causes also account for the majority of deaths among patients with predialysis kidney disease.1,2 The burden of cardiovascular disease in this patient population is evident upon the initiation of renal replacement therapy. As shown in a Canadian cohort, 40% of patients starting dialysis already had evidence of coronary heart disease (CHD), and only 16% had normal echocardiographic studies.3 Early intervention is required to minimize the burden of cardiovascular disease in CKD. Risk reduction strategies are likely to be effective in reducing cardiovascular morbidity and mortality in CKD patients in the same way these interventions improve outcomes in the general population. However, the pathogenesis of cardiovascular damage in CKD patients is far more complex than in the general population and includes traditional risk factors as well as risk factors typical of chronic renal failure (Table 1).1 Thus, risk reduction in these patients should target both traditional and CKD-specific risks for cardiovascular disease. Traditional cardiovascular risk factors are highly prevalent in patients with chronic renal insufficiency. Diabetes is the most common cause of kidney disease in the United States and is the primary diagnosis in 45% of ESRD patients.4 The total burden of diabetes in patients surviving 1 year on dialysis was actually 60%.4 Similarly, hypertension and dyslipidemia are rampant in this population. In a cross-sectional analysis involving patients enrolled in the Modification of Diet in Renal Disease trial, 64% were hypertensive despite being on therapy, 64% had low-density lipoprotein (LDL) cholesterol levels greater than 130 mg/dL, and 38.3% had high-density lipoprotein (HDL) cholesterol levels less than 35 mg/dL.5

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CKD-related risk factors for cardiovascular disease include the hemodynamic and metabolic abnormalities associated with renal insufficiency and the complications of decreased renal function. These risk factors are sometimes divided into those altered by the uremic state (eg, hypertension, dyslipidemia) and those characteristic of the uremic state (eg, anemia, oxidative stress) (Table 1).1 Whether renal insufficiency itself is an independent risk factor for cardiovascular disease is unclear. The Heart Outcomes and Prevention Evaluation study demonstrated an increased incidence of cardiovascular death, myocardial infarction (MI), or stroke in patients with renal insufficiency, and this incidence increased with serum creatinine concentration.6 Other data from intervention studies in patients with hypertension, coronary disease, and congestive heart failure show a consistent role of renal dysfunction in predicting worse cardiovascular outcomes and death.7 Conversely, Garg et al8 found no independent association between moderate renal insufficiency and total as well as cardiovascular mortality after adjustment for coexisting risk factors in a large prospective cohort. Despite these conflicting data, we believe that a sufficient number of studies suggest an independent role of CKD in predicting cardiovascular risk, such that patients with CKD should be considered at highest risk for subsequent cardiovascular events. This article outlines relevant cardiovascular risk factors in patients with CKD and summarizes the available evidence supporting the role of these factors

Dr. Zaldivar is a Fellow, Division of Nephrology, University of Connecticut Health Center, Farmington, CT. Dr. Peixoto is an Assistant Professor of Medicine, Section of Nephrology, Yale University School of Medicine, New Haven, CT; and Director, Hypertension Clinic, VA Connecticut Healthcare System, West Haven, CT. Dr. Perazella is an Associate Professor of Medicine, Section of Nephrology; and Director, Acute Dialysis Program, Yale University School of Medicine; he is also a member of the Hospital Physician Editorial Board.

Hospital Physician June 2003

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Zaldivar & Peixoto : CV Risk Reduction in CKD : pp. 29 – 35, 50

Table 1. Cardiovascular Risk Factors in Chronic Kidney Disease Traditional Risk Factors

Risk Factors Altered by Uremia

UremiaRelated Risk Factors

Hypertension

Dyslipidemia

Hyperlipidemia

High lipoprotein (a) levels

Hemodynamic overload

Diabetes mellitus Tobacco use Physical inactivity

Anemia

Prothrombotic factors

Increased oxidative stress

Hyperhomocysteinemia

Malnutrition

Hypertension Sleep apnea

Hyperparathyroidism Elevated ADMA levels

Adapted with permission from Parfey PS, Foley RN. The clinical epidemiology of cardiac disease in chronic renal failure. J Am Soc Nephrol 1999;10:1607. ADMA = asymmetric dimethyl arginine.

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in development of cardiovascular disease. Data in support of strategies to reduce cardiovascular risks in renal patients also are highlighted. Although CKD and ESRD patients are somewhat different populations, the limited availability of data on cardiovascular outcomes in pre-ESRD demands that our discussion include both patient groups. TRADITIONAL RISK FACTORS Hypertension Hypertension is a common problem in CKD patients, and evidence strongly supports an association between hypertension and the occurrence of vascular events in this population.9,10 However, the data on hypertension and mortality in dialysis patients are potentially misleading. In this group, a U effect (ie, increased mortality at both ends of the spectrum of blood pressure) has been observed in multiple studies, implying that lower blood pressure levels are markers of worse outcomes.11,12 More recent studies with adjustment for comorbidities have suggested that a large portion of this effect is due to the presence of underlying cardiac disease.13 Patients with a large burden of preexisting vascular disease are likely to die earlier in the course of ESRD, whereas those who survive longer than 5 years on dialysis experience a more substantial impact of hypertension on outcomes.14 Thus, the effects of hypertension on cardiovascular disease in CKD appear to be longer term and may be overshadowed by the impact of other serious coexisting conditions.

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Identification and treatment of hypertension is important in CKD to slow the decline in renal function. Generally speaking, better blood pressure control will slow the progression of all types of kidney disease. In proteinuric diseases, tight blood pressure control (ie, to levels < 125/75 mm Hg) has been shown to significantly slow the decline of renal function.15 However, in the case of minimally proteinuric diseases (eg, hypertensive nephrosclerosis, polycystic kidney disease), no additional renal benefit has been achieved by lowering blood pressure below the usual 140/90 mm Hg target.16,17 From a cardiovascular perspective, it is less clear that specific hypertension management approaches will improve cardiovascular outcomes in CKD patients. In stages 3 and 4 CKD (ie, pre-ESRD), antihypertensive therapy improves left ventricular hypertrophy (LVH),18 and a recent study of patients with polycystic kidney disease revealed greater reduction of LVH (35% versus 21%) in patients with aggressive blood pressure lowering (target of 120/80 mm Hg) compared with patients conventionally treated (target of 140/90 mm Hg).17 Available prospective data from the CKD population do not suggest improvement in cardiovascular morbidity or mortality with any particular type of drug therapy. In one study of patients with diabetic nephropathy, however, an angiotensin II type 1 receptor blocker (ie, losartan) decreased the rate of first hospitalization for a heart failure episode compared with conventional therapy.19 As for dialysis patients, interventional data are scarce. However, analyses of large cohort studies have revealed a protective effect with the use of (any) antihypertensive medication,11,20 and exposure to calcium channel blockers or β-blockers has been associated with decreased cardiovascular death in hemodialysis patients.13,21 Results with angiotensin-converting enzyme (ACE) inhibitors have been inconsistent across studies, and the 2 largest databases do not reveal any specific protective effect on mortality.13,21 In one of the rare prospective randomized trials in this population, carvedilol was shown to improve symptoms and left ventricular ejection fraction in hemodialysis patients with moderate-to-severe congestive heart failure.22 There was no effect on mortality in this 1-year study. In summary, from a strict cardiovascular perspective, it is not clear that drug choice affects outcomes in the CKD population. Interventional studies with longer follow-up and primary cardiovascular endpoints are needed to adequately address this question. Diabetes Mellitus A large proportion of patients with CKD has diabetes. Diabetes is a significant risk factor for cardiovascular disease, and this risk is even higher in diabetic



patients with renal complications. In patients without significant renal dysfunction, several studies have correlated markers of diabetic nephropathy with cardiovascular outcomes. For example, the World Health Organization Multinational Study of Vascular Disease in Diabetes demonstrated an almost 2-fold increase in the standardized mortality ratios in diabetic patients with microalbuminuria compared with the general population.23 The mortality risk for patients with both microalbuminuria and hypertension increased to 2- to 3-fold, depending on sex. The risk for cardiovascular events extends to more advanced degrees of renal failure, so that diabetes is an independent risk factor for the development of de novo ischemic heart disease and de novo heart failure in dialysis patients.1 Although these findings suggest only associations between diabetic nephropathy with cardiovascular outcomes and no intervention data are currently available in CKD, it is reasonable to attempt to achieve tight glycemic control (ie, glycosylated hemoglobin concentration of 7%) in CKD patients with diabetes. Smoking Previous studies have demonstrated that smoking further aggravates the excessive cardiovascular risk in patients with impaired renal function.24 Stack and Bloembergen25 noted in a random sample of new ESRD patients in the United States that smokers had a 22% greater risk of developing coronary artery disease. Kawagishi et al26 found a correlation between carotid artery intima media thickness and smoking in patients on maintenance hemodialysis. In another study, the predictive ability of smoking for carotid atherosclerosis in dialysis patients was similar to that of hypercholesterolemia and age.27 Thus, smoking has a clear association with cardiovascular disease in CKD, and attempts to modify this behavior seem warranted. To our knowledge, no published studies have reported on the efficacy of specific smoking cessation strategies in patients with CKD or ESRD. However, we believe that smoking cessation is an important preventive intervention, and we anecdotally have used nicotine replacement as a patch or gum in such patients, with results similar to those in the general population (ie, response rates of 9% to 35%).28 There are no studies of bupropion for smoking cessation in patients with CKD. Physical Inactivity The benefits of exercise in the general population are well established, but studies of exercise in CKD patients are few. Exercise has been shown to improve blood pressure control in patients with CKD.29 In ESRD


patients on hemodialysis, exercise has been associated with improvements in blood pressure control as well as insulin sensitivity.30 Patients who commence an exercise program also report small but significant changes in physical functioning.31 Exercise programs, however, have not been shown to improve lipid profiles in patients with CKD29 or ESRD.32 Furthermore, adherence to an exercise prescription is limited due to the CKD patients’ significant chronic ailment.29 Nevertheless, the potential physical and emotional benefits of exercise justify an attempt at this intervention in all patients with CKD, provided the chosen physical activities are deemed safe from cardiovascular and musculoskeletal standpoints. RISK FACTORS ALTERED BY UREMIA Dyslipidemia The prevalence of hyperlipidemia is higher in CKD patients than in the general population but varies depending on the specific lipid measured, target population, course of renal disease, and level of renal function. Total and LDL cholesterol levels are increased most often in patients with chronic renal insufficiency and nephrotic syndrome, in patients treated by peritoneal dialysis, and in renal transplant recipients.33 Uremic dyslipidemia is common in ESRD patients and is characterized by increased plasma triglyceride levels (due to elevated very-low-density lipoproteins and intermediate-density lipoproteins), decreased HDL levels, and normal LDL levels. Triglyceride and HDL levels have been found to be more markedly abnormal in individuals with more severe renal insufficiency. Other plasma lipoprotein changes found in ESRD patients include triglyceride-enrichment of LDL and HDL and increased levels of lipoprotein (a).34 Few studies have examined the relationship between lipid abnormalities and cardiovascular disease in chronic renal insufficiency. Jungers et al9 prospectively examined the relationship between serum lipids and the incidence of MI in 147 patients with creatinine clearance of 20 to 50 mL/min/1.73 m2. The incidence of MI was approximately 2.5 times higher than in the general population. The 41 patients who developed MI had lower HDL cholesterol levels and higher levels of triglycerides, LDL cholesterol, apolipoprotein B, and lipoprotein (a).9 In April 2003, the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) Work Group published clinical practice guidelines for managing dyslipidemia in CKD.35 According to these guidelines, the most recent recommendations of the National Cholesterol Education Program Expert Panel36 can be used to guide treatment for hyperlipidemia in


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patients with CKD stages 1 through 4 (pre-ESRD). Patients with CKD should be considered in the highest risk group. Dietary or pharmacologic therapy should be initiated at LDL cholesterol levels greater than 100 or 130 mg/dL, respectively, with a therapeutic goal of less than 100 mg/dL.36 Dietary therapy is effective in reducing total and LDL cholesterol levels as well as triglyceride levels, but the effects are limited.36 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (also called statins) are the most effective of all currently available medications for reducing total and LDL cholesterol and have been associated with decreased mortality in a cohort of hemodialysis patients.37 Patients with elevated triglyceride levels or low HDL levels should initially be treated with therapeutic lifestyle changes unless LDL levels are also increased.36 If therapeutic lifestyle changes are insufficient, fibric acid analogs are the most effective agents for reducing triglyceride levels in patients with CKD.35 Caution should be exercised when using these agents in higher doses or in combination due to increased risk of myopathy in patients with renal disease. Hyperhomocysteinemia Emerging evidence suggests a dose-dependent relationship between plasma homocysteine levels and the risk for atherosclerosis in the general population, and this link appears to be independent of other risk factors.38 Hyperhomocysteinemia is highly prevalent in CKD patients, with a possible relationship to increased atherosclerosis in this population as well.39 It is estimated that approximately 90% of patients with ESRD have elevated plasma homocysteine levels, likely as a result of impaired homocysteine metabolism.40 The clinical impact of lowering homocysteine levels via high-dose folate, vitamin B6, and vitamin B12 supplementation still must be assessed; conventional doses seldom correct the abnormal levels observed in advanced kidney disease.39,40 Although previous, primarily prospective studies have looked at absolute reduction of homocysteine levels with high-dose supplementation, there have been no randomized studies measuring clinical outcomes. A large Veterans Affairs–based multicenter trial (the Homocysteine Study) is underway to address the question of whether high-dose folate supplementation decreases cardiovascular endpoints in CKD and ESRD. Another multicenter trial that is in progress involves renal transplant recipients with hyperhomocysteinemia who are being treated with high-dose folic acid and vitamin B–based therapy. These 2 studies should provide answers on the value of homocysteine-lowering interventions within the next few years.


UREMIA-RELATED RISK FACTORS Anemia Under normal conditions, anemia leads to reversible increased cardiac output and blood flow. In effect, there is an increase in left ventricular diastolic diameter and volume and a subsequent increase in left ventricular wall tension, leading to adaptive hypertrophy and remodeling. Under uremic conditions, these changes become maladaptive, resulting in irreversible hypertrophy and arteriosclerosis.41 Early intervention to address anemia, therefore, is important to mitigate cardiovascular damage in the CKD patient. A growing body of evidence supports the role of anemia as a correlate of left ventricular growth and, therefore, a cardiac risk factor in CKD patients, beginning at the early stages of renal disease.42,43 In predialysis patients, anemia has been shown to correlate with left ventricular growth.43 In a Canadian cohort of predialysis patients with renal insufficiency, a 0.5 g/dL decrease in hemoglobin level was associated with a 32% increase in the risk of left ventricular growth.43 Studies in dialysis patients indicate that anemia is associated with increased cardiovascular morbidity and higher mortality. For example, in ESRD dialysis patients, each 1 g/dL decrease in hemoglobin was independently associated with increases in the presence of LVH on echocardiography (50%), the development of new or recurrent heart failure (relative risk of 1.28 or 1.2, respectively), and mortality (18% to 25%).44 A retrospective study of nearly 100,000 dialysis patients showed that improved survival was associated with sustained increases in hematocrit levels.45 In one study, regression of LVH was demonstrated in predialysis patients after 12 months of erythropoietin treatment aimed at normalizing hematocrit, without negative effects on renal function or blood pressure control.46 However, in another study performed in hemodialysis patients this was not the case; normalization of hemoglobin levels was found to have little effect on left ventricular morphology once dilatation had occurred.47 While the hemoglobin/hematocrit safety ceiling and target levels of erythropoietin therapy are under debate, a target hemoglobin level of 12 g/dL seems to be appropriate and safe for most patients at any stage of CKD, provided that a rapid increase is avoided and blood pressure is carefully controlled.48,49 Because erythropoietin therapy has been shown to raise blood pressure in up to 30% of dialysis patients, there is concern that an untreated rise in blood pressure will increase cardiac workload and exacerbate cardiovascular disease. Moreover, the correction of anemia



improves uremic coagulopathy, increases blood viscosity, and reduces erythrocyte deformability, thereby enhancing the potential for thrombus formation.49 Thus, a conservative approach that can be employed safely and easily in most patients would be to increase hemoglobin levels by no more than 1 g/dL per month. Another unresolved issue in the management of anemia in CKD is whether iron supplementation may create cardiovascular problems in the long term. This issue is particularly relevant to dialysis patients receiving large doses of parenteral iron. While awaiting illuminating data on the risk/benefit ratio of aggressive iron support of erythropoiesis, it is reasonable not to exceed ferritin levels of 500 ng/mL.49 Hyperparathyroidism Disturbances of calcium and phosphate metabolism may play a role in cardiovascular disease in patients with CKD. Elevated serum calcium and phosphate, secondary hyperparathyroidism, administration of phosphatechelating agents, and vitamin D supplementation have been implicated, but the effect of these different factors on the cardiovascular system is incompletely understood.1,49 Common pathologic findings in uremic hearts include calcifications of the coronary arteries, valves, and myocardial tissue, as well as diffuse myocardial fibrosis.50 Animal studies have shown that parathyroid hormone (PTH) increases the cellular burden of calcium and activates fibroblasts. Primary and secondary hyperparathyroidism have been associated with increased myocardial calcium content in humans, but the clinical consequences of secondary hyperparathyroidism are less clear. The improvement in cardiac function after parathyroidectomy has not been consistently demonstrated in studies.50 Excessive plasma PTH probably plays a prominent role in diffuse arterial media calcification and is one factor among many others in the pathogenesis of patchy intimal and subintimal calcification.41,50 No data are available linking increased PTH concentrations to primary endpoints such as survival and cardiovascular morbidity. In contrast to the absence of a direct link between PTH and prognosis, hyperphosphatemia has been found to be strongly associated with mortality in dialyzed ESRD patients.51 The adjusted relative risk of death was found to be greater at serum phosphate levels greater than 6.5 mg/dL and when the calcium and phosphate product was greater than 72 mg2/dL2. The increased mortality in hyperphosphatemic patients was shown to be due to an increase in cardiac deaths. There are no interventional data yet available on treat-


ment of hyperphosphatemia and primary endpoints. However, a recent study demonstrated less progression of coronary and valvular calcifications in patients randomized to sevelamer (a noncalcium polymer that also has a lipid-lowering effect) as the primary binder than in those randomized to calcium carbonate or acetate.52 These data implicate the urgency of treating hyperphosphatemia to prevent cardiac death during the early stages of chronic renal failure. Similarly, treatment of secondary hyperparathyroidism also may afford some cardiovascular benefit. Efforts should be made to reduce PTH secretion through strict phosphorus control (diet and binders) and judicious use of vitamin D derivatives. Use of a noncalcium-containing binder (eg, sevelamer) may have additional benefits from a cardiovascular standpoint. EMERGING RISK FACTORS Growing evidence supports the role of vessel wall inflammation and malnutrition in the initiation and progression of atherosclerosis—the so-called malnutritioninflammation-atherosclerosis syndrome.53 Stenvinkel et al54 found a higher prevalence of malnutrition in patients with chronic renal failure compared with healthy controls. Malnourished patients in turn had increased levels of C-reactive protein, higher calculated carotid intima media areas, and a higher prevalence of carotid plaques compared with well-nourished patients. Zimmermann et al55 found age and C-reactive protein to be powerful independent predictors of both overall death and cardiovascular death in hemodialysis patients. Pecoits-Filho et al56 analyzed other markers of chronic inflammation and found that patients with the highest levels of interleukin-6 at initiation of dialysis had an increase in mortality after an average of 3.1 years of follow-up, and this effect was independent of multiple other risk factors. Though teleologically sound, it has not yet been determined that timedependent improvement in nutritional status improves cardiovascular outcomes. Metabolic waste products accumulating in chronic renal failure may contribute to elevated cardiovascular risk. The endogenous competitive nitric oxide synthase inhibitor, asymmetric dimethyl arginine, has been shown to accumulate in chronic renal failure and inhibits nitric oxide–induced vasodilatation, thereby contributing to hypertension and cardiovascular disease.57 More studies are needed to understand how this factor may be modified. Activation of the sympathetic nervous system has long been documented in patients with CKD.58 However, it was not until recently that a prognostic relevance


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of this hyperactivity was demonstrated. Zoccali et al59 showed that hemodialysis patients with plasma norepinephrine levels above the 75th percentile of the distribution had a nearly 2-fold increase in relative risk of cardiovascular complications. Sleep apnea is also a common complication of ESRD and has been associated with increased left ventricular mass60 as well as increased risk for cardiovascular events.61 Because more intensive dialysis has been shown to improve dialysis-associated sleep-disordered breathing,62 future research will be needed to independently demonstrate the value of such intervention on improvement of outcomes. Because sleep apnea in ESRD patients is a combination of central and obstructive components, it is not clear what value noninvasive positivepressure ventilation would have on a large scale. CONCLUSION In conclusion, patients with CKD have both traditional and nontraditional (ie, uremia-related) risk factors for cardiovascular disease, and early intervention may reduce the burden of disease in these patients. Cardiovascular disease should be a concern even in the early stages of CKD, long before patients are referred to nephrologists or considered for renal replacement therapy. The primary care provider should seek to identify and modify those risk factors that will significantly affect the cardiovascular morbidity and mortality of CKD patients. While some risk factors cannot be easily modified, the risks from hypertension, smoking, physical inactivity, hyperlipidemia, anemia, and hyperparathyroidism could be reduced with early intervention. HP REFERENCES 1. National Kidney Foundation (NKF) Kidney Disease Outcome Quality Initiative (K/DOQI) Advisory Board. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Kidney Disease Outcome Quality Initiative. Am J Kidney Dis 2002;39(2 Suppl 2):S1–246. 2. Wannamethee SG, Shaper AG, Perry IJ. Serum creatinine concentration and risk of cardiovascular disease: a possible marker for increased risk of stroke. Stroke 1997; 28:557–63. 3. Harnett JD, Foley RN, Kent GM, et al. Congestive heart failure in dialysis patients: prevalence, incidence, prognosis and risk factors. Kidney Int 1995;47:884–90. 4. Excerpts from the United States Renal Data System 2002 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. III. Patient characteristics. Am J Kidney Dis 2003;41(4 Suppl 2):S57–70. 5. Sarnak MJ, Coronado BE, Greene T, et al. Cardiovascular disease risk factors in chronic renal insufficiency. Clin Nephrol 2002;57:327–35.


6. Mann JF, Gerstein HC, Pogue J, et al. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial. Ann Intern Med 2001;134:629–36. 7. Ruilope LM, van Veldhuisen DJ, Ritz E, Luscher TF. Renal function: the Cinderella of cardiovascular risk profile. J Am Coll Cardiol 2001;38:1782–7. 8. Garg AX, Clark WF, Haynes RB, House AA. Moderate renal insufficiency and the risk of cardiovascular mortality: results from the NHANES I. Kidney Int 2002;61:1486–94. 9. Jungers P, Massy ZA, Khoa TN, et al. Incidence and risk factors of atherosclerotic cardiovascular accidents in predialysis chronic renal failure patients: a prospective study. Nephrol Dial Transplant 1997;12:2597–602. 10. Mailloux LU, Levey AS. Hypertension in chronic renal disease. Am J Kidney Dis 1998;32(Suppl 3):S120–S141. 11. Zager PG, Nikolic J, Brown RH, et al. “U” curve association of blood pressure and mortality in hemodialysis patients. Medical Directors of Dialysis Clinic, Inc. Kidney Int 1998;54:561–9. 12. Port FK, Hulbert-Shearon TE, Wolfe RA, et al. Predialysis blood pressure and mortality risk in a national sample of maintenance hemodialysis patients. Am J Kidney Dis 1999;33:507–17. 13. Foley RN, Herzog CA, Collins AJ. Blood pressure and long-term mortality in United States hemodialysis patients: USRDS Waves 3 and 4 Study. Kidney Int 2002;62: 1784–90. 14. Mazzuchi N, Carbonell E, Fernandez-Cean J. Importance of blood pressure control in hemodialysis patient survival. Kidney Int 2000;58:2147–54. 15. Klahr S, Levey AS, Beck GJ, et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med 1994; 330:877–84. 16. Wright JT Jr, Bakris G, Greene T, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA 2002;288:2421–31. 17. Schrier R, McFann K, Johnson A, et al. Cardiac and renal effects of standard versus rigorous blood pressure control in autosomal-dominant polycystic kidney disease: results of a seven-year prospective randomized study. J Am Soc Nephrol 2002;13:1733–9. 18. Levey AS, Beto JA, Coronado BE, et al. Controlling the epidemic of cardiovascular disease in chronic renal disease: what do we know? What do we need to learn? Where do we go from here? National Kidney Foundation Task Force on Cardiovascular Disease. Am J Kidney Dis 1998; 32:853–906. 19. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861–9. 20. Salem MM, Bower J. Hypertension in the hemodialysis population: any relation to one-year survival? Am J



Kidney Dis 1996;28:737–40. 21. Kestenbaum B, Gillen DL, Sherrard DJ, et al. Calcium channel blocker use and mortality among patients with end-stage renal disease. Kidney Int 2002;61:2157–64. 22. Cice G, Ferrara L, Di Benedetto A, et al. Dilated cardiomyopathy in dialysis patients—beneficial effects of carvedilol: a double-blind, placebo-controlled trial. J Am Coll Cardiol 2001;37:407–11. 23. Wang SL, Head J, Stevens L, Fuller JH. Excess mortality and its relation to hypertension and proteinuria in diabetic patients. The world health organization multinational study of vascular disease in diabetes. Diabetes Care 1996;19:305–12. 24. Orth SR, Ritz E. The renal risks of smoking: an update. Curr Opin Nephrol Hypertens 2002;11:483–8. 25. Stack AG, Bloembergen WE. Prevalence and clinical correlates of coronary artery disease among new dialysis patients in the United States: a cross-sectional study. J Am Soc Nephrol 2001;12:1516–23. 26. Kawagishi T, Nishizawa Y, Konishi T, et al. High-resolution B-mode ultrasonography in evaluation of atherosclerosis in uremia. Kidney Int 1995;48:820–6. 27. Malatino LS, Benedetto FA, Mallamaci F, et al. Smoking, blood pressure and serum albumin are major determinants of carotid atherosclerosis in dialysis patients. CREED Investigators. Cardiovascular Risk Extended Evaluation in Dialysis patients. J Nephrol 1999;12:256–60. 28. Watts SA, Noble SL, Smith PO, Disco M. First-line pharmacotherapy for tobacco use and dependence. J Am Board Fam Pract 2002;15:489–97. 29. Boyce ML, Robergs RA, Avasthi PS, et al. Exercise training by individuals with predialysis renal failure: cardiorespiratory endurance, hypertension, and renal function. Am J Kidney Dis 1997;30:180–92. 30. Goldberg AP, Geltman EM, Hagberg JM, et al. Therapeutic benefits of exercise training for hemodialysis patients. Kidney Int Suppl 1983;16:S303–9. 31. Painter P, Carlson L, Carey S, et al. Low-functioning hemodialysis patients improve with exercise training. Am J Kidney Dis 2000;36:600–8. 32. Stephens R, Williams A, McKnight T, Dodd S. Effects of self-monitored exercise on selected blood chemistry parameters of end-stage renal disease patients. Am J Phys Med Rehabil 1991;70:149–53. 33. Kasiske BL. Hyperlipidemia in patients with chronic renal disease. Am J Kidney Dis 1998;32(5 Suppl 3):S142–56. 34. Quaschning T, Krane V, Metzger T, Wanner C. Abnormalities in uremic lipoprotein metabolism and its impact on cardiovascular disease. Am J Kidney Dis 2001; 38(4 Suppl 1):S14–9. 35. K/DOQI Clinical Practice Guidelines for Managing Dyslipidemias in Chronic Kidney Disease. III. Treating dyslipidemias. Am J Kidney Dis 2003;41(4 Suppl 3):S39–58. 36. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). Expert

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486–97. Seliger SL, Weiss NS, Gillen DL, et al. HMG-CoA reductase inhibitors are associated with reduced mortality in ESRD patients. Kidney Int 2002;61:297–304. Eikelboom JW, Lonn E, Genest J Jr, et al. Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence. Ann Intern Med 1999;131:363–75. Bostom AG, Shemin D, Gohh RY, et al. Treatment of hyperhomocysteinemia in hemodialysis patients and renal transplant recipients. Kidney Int Suppl 2001;78:S246–52. Shemin D, Bostom AG, Selhub J. Treatment of hyperhomocysteinemia in end-stage renal disease. Am J Kidney Dis 2001;38(4 Suppl 1):S91–4. London G. Pathophysiology of cardiovascular damage in the early renal population. Nephrol Dial Transplant 2001;16 Suppl 2:3–6. Portoles J. The beneficial effects of intervention in early renal disease. Nephrol Dial Transplant 2001;16 Suppl 2: 12–5. Levin A, Thompson CR, Ethier J, et al. Left ventricular mass index increase in early renal disease: impact of decline in hemoglobin. Am J Kidney Dis 1999;34:125–34. Foley RN, Parfrey PS, Harnett JD, et al. The impact of anemia on cardiomyopathy, morbidity, and mortality in end-stage renal disease. Am J Kidney Dis 1996;28:53–61. Ma JZ, Ebben J, Xia H, Collins AJ. Hematocrit level and associated mortality in hemodialysis patients. J Am Soc Nephrol 1999;10:610–9. Hayashi T, Suzuki A, Shoji T, et al. Cardiovascular effect of normalizing the hematocrit level during erythropoietin therapy in predialysis patients with chronic renal failure. Am J Kidney Dis 2000;35:250–6. Foley RN, Parfrey PS, Morgan J, et al. Effect of hemoglobin levels in hemodialysis patients with asymptomatic cardiomyopathy. Kidney Int 2000;58:1325–35. Portoles J, Torralbo A, Martin P, et al. Cardiovascular effects of recombinant human erythropoietin in predialysis patients. Am J Kidney Dis 1997;29:541–8. Locatelli F, Bommer J, London GM. Cardiovascular disease determinants in chronic renal failure: clinical approach and treatment. Nephrol Dial Transplant 2001;16: 459–68. Rostand SG, Drueke TB. Parathyroid hormone, vitamin D, and cardiovascular disease in chronic renal failure. Kidney Int 1999;56:383–92. Block GA, Hulbert-Shearon TE, Levin NW, Port FK. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 1998;31:607–17. Chertow GM, Burke SK, Raggi P. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int 2002;62:245–52. Pecoits-Filho R, Lindholm B, Stenvinkel P. The malnutrition, inflammation, and atherosclerosis (MIA) syndrome—the heart of the matter. Nephrol Dial Transplant 2002;17 Suppl 11:28–31. (continued on page 50)



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Zaldivar & Peixoto : CV Risk Reduction in CKD : pp. 29 – 35, 50 (from page 35)

54. Stenvinkel P, Heimburger O, Paultre F, et al. Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. Kidney Int 1999; 55:1899–911. 55. Zimmermann J, Herrlinger S, Pruy A, et al. Inflammation enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int 1999;55:648–58. 56. Pecoits-Filho R, Barany P, Lindholm B, et al. Interleukin6 is an independent predictor of mortality in patients starting dialysis treatment. Nephrol Dial Transplant 2002;17:1684–8. 57. Zoccali C, Bode-Boger S, Mallamaci F, et al. Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study. Lancet 2001;358:2113–7. 58. Converse RL Jr, Jacobsen TN, Toto RD, et al. Sympa-

59.

60.

61.

62.

thetic overactivity in patients with chronic renal failure. N Engl J Med 1992;327:1912–8. Zoccali C, Mallamaci F, Parlongo S, et al. Plasma norepinephrine predicts survival and incident cardiovascular events in patients with end-stage renal disease. Circulation 2002;105:1354–9. Zoccali C, Benedetto FA, Tripepi G, et al. Nocturnal hypoxemia, night-day arterial pressure changes and left ventricular geometry in dialysis patients. Kidney Int 1998; 53:1078–84. Zoccali C, Mallamaci F, Tripepi G. Nocturnal hypoxemia predicts incident cardiovascular complications in dialysis patients. J Am Soc Nephrol 2002;13:729–33. Hanly PJ, Pierratos A. Improvement of sleep apnea in patients with chronic renal failure who undergo nocturnal hemodialysis. N Engl J Med 2001;344:102–7.

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